Centro de Investigación en Nutrición y Salud Pública, Facultad de Salud Pública y Nutrición, Universidad Autonoma de Nuevo Leon, Monterrey 66460, Mexico.
Int J Mol Sci. 2022 Jul 4;23(13):7437. doi: 10.3390/ijms23137437.
The origin of cancer remains one of the most important enigmas in modern biology. This paper presents a hypothesis for the origin of carcinomas in which cellular aging and inflammation enable the recovery of cellular plasticity, which may ultimately result in cancer. The hypothesis describes carcinogenesis as the result of the dedifferentiation undergone by epithelial cells in hyperplasia due to replicative senescence towards a mesenchymal cell state with potentially cancerous behavior. In support of this hypothesis, the molecular, cellular, and histopathological evidence was critically reviewed and reinterpreted when necessary to postulate a plausible generic series of mechanisms for the origin and progression of carcinomas. In addition, the implications of this theoretical framework for the current strategies of cancer treatment are discussed considering recent evidence of the molecular events underlying the epigenetic switches involved in the resistance of breast carcinomas. The hypothesis also proposes an epigenetic landscape for their progression and a potential mechanism for restraining the degree of dedifferentiation and malignant behavior. In addition, the manuscript revisits the gradual degeneration of the nonalcoholic fatty liver disease to propose an integrative generalized mechanistic explanation for the involution and carcinogenesis of tissues associated with aging. The presented hypothesis might serve to understand and structure new findings into a more encompassing view of the genesis of degenerative diseases and may inspire novel approaches for their study and therapy.
癌症的起源仍然是现代生物学中最重要的谜团之一。本文提出了一个关于癌发生的假说，其中细胞衰老和炎症使细胞可塑性得以恢复，这最终可能导致癌症。该假说将癌发生描述为上皮细胞在复制性衰老导致的增生中经历去分化，向具有潜在致癌行为的间充质细胞状态的过程。为了支持这一假说，本文对分子、细胞和组织病理学证据进行了批判性审查，并在必要时进行了重新解释，以假设癌发生和进展的一系列合理通用机制。此外，考虑到涉及乳腺癌耐药性的表观遗传开关所涉及的分子事件的最新证据，本文还讨论了这一理论框架对当前癌症治疗策略的影响。该假说还提出了一个用于其进展的表观遗传景观，以及一种用于限制去分化和恶性行为程度的潜在机制。此外，本文还重新审视了非酒精性脂肪性肝病的逐渐退化，以提出一个与衰老相关的组织退化和癌发生的综合机制解释。提出的假说可以帮助理解和构建新发现，形成对退行性疾病发生的更全面的认识，并为这些疾病的研究和治疗提供新的方法。
